Increased Dispersion Of Repolarization Research Articles

Drug-induced increase in dispersion of ventricular repolarization in patients with heart failure with preserved ejection fraction

BackgroundHeart failure (HF) with preserved ejection fraction (HFpEF) is associated with enhanced response to drug-induced QT interval lengthening. We determined the influence of HFpEF on drug-induced lengthening of dispersion of repolarization, a measure of proarrhythmic risk. MethodsWe administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched controls without HF. Twelve‑lead electrocardiograms were obtained prior to ibutilide and serially for 8 h post-ibutilide. Tpeak-Tend, a measure of dispersion of ventricular repolarization, and heart rate-corrected J-Tpeak (J-Tpeakc), representing early repolarization, were measured by an investigator blinded to study groups. ResultsBaseline (pre-ibutilide) Tpeak-Tend and J-Tpeakc were not significantly different in the HFpEF and control groups. Maximum Tpeak-Tend was longer in the HFpEF group than in the control group (85 ± 10 vs 73 ± 8 ms, p = 0.01). Additionally, % change from baseline in Tpeak-Tend was greater in the HFpEF group [median (IQR) 17 (11) vs 8 (3)%, p = 0.003]. The area under the effect curve from 0 to 8 hours following ibutilide (including the 10-minute infusion) (AUEC0-8.17) for Tpeak-Tend was also larger in the HFpEF group (600 ± 42 vs. 543 ± 49 ms•hr, p = 0.03). Maximum J-Tpeakc, % change from baseline in J-Tpeakc and AUEC0-8.17 for J-Tpeakc in the two groups were not significantly different. ConclusionHFpEF is associated with enhanced response to drug-induced increases in dispersion of repolarization.

PO-01-180 MECHANISMS OF PULMONARY ARTERIAL HYPERTENSION-INDUCED ATRIAL FIBRILLATION IN THE RIGHT HEART: INSIGHTS FROM MULTI-SCALE MODELS OF THE HUMAN ATRIA

Pulmonary arterial hypertension (PAH) is one of the common conditions primarily affecting the right heart and promoting atrial fibrillation (AF), but the mechanisms are poorly understood. This study aimed to use multi-scale atrial models to investigate mechanisms by which right atrial (RA) remodeling facilitates and perpetuates atrial arrhythmias. We have developed single-cell-to-tissue-level computer models to mimic control and disease conditions by incorporating the most recent experimental data on PAH-induced electrical and structural remodeling (Hiram et al., JACC, 2019). The effects of PAH-induced remodeling in both RA and left atria (LA) on action potential duration (APD), calcium transient (CaT), conduction velocity (CV), and dynamics of re-entrant excitation waves were assessed using the multi-scale computer models. Our computer simulation results suggested that at the single cell level, although PAH-induced remodeling prolonged action potential (ΔAPD: 49.6 ms in the RA vs. 41.6 ms in the LA) and increased calcium transient (ΔCaT: 7.5e-2 μM in the RA vs. 0.9e-3 μM in the LA), heterogeneous remodeling increased susceptibility to afterdepolarizations only in the RA (Fig. A). At the tissue level, dramatically reduced CV (ΔCV: -0.5 m/s in the RA vs. -0.05 m/s in the LA) abbreviated wavelength inthe RA but not inthe LA. In addition, afterdepolarizations in the RA increased repolarization dispersion and promoted unidirectional conduction block (Fig B). Finally, the upregulated fibrosis increased the chance of breakdown of excitation waves and sustained reentries in in the RA (Fig C). These results demonstrated that PAH-induced AF is mainly in RA not LA, due to a higher degree of cardiac remodeling. RA remodeling increases arrhythmias risk due to elevated susceptibility to afterdepolarizations, reduced wavelength, increased repolarization heterogeneity and upregulation of fibrosis, which together facilitate initiation and maintenance of re-entrant circuits in the right heart.

Cardiac remodeling accompanied by increased arrhythmia susceptibility in a dog model of chronic high-intensity endurance training

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by NKFIH grants (K-19992, K-135464) and GINOP-2.3.2-15-2016-00047. Background Despite the cardiovascular benefits of regular physical exercise, chronic high-level exercise can evoke malignant arrhythmias, including ventricular fibrillation and even sudden cardiac death, especially in young top athletes. In some cases the underlying mechanisms are unclear. Objectives The goal of this study was to assess mechanisms underlying cardiac structural-electrical changes and arrhythmia vulnerability by high-level vigorous exercise training in animal species that are electrophysiologically relevant to the human heart. Methods Beagle dogs were randomly assigned to matched sedentary (Sed) or intensive exercise-training (Ex) groups (n=12-12). Ex dogs underwent a 4-month-long intensive treadmill-running protocol (5 days a week, 6 hours a day at a speed of 14-21 km/h with an inclination from 5% to 12%). In vivo echocardiography and electrophysiological measurements were performed. Proarrhythmic sensitivity was tested and the autonomic alterations were examined. At study end, arrhythmia susceptibility was tested with high-frequency burst stimulation in open-chest anaesthetized dogs. This was followed by cardiac excision and cardiomyocyte isolation, formalin preservation for histology, snap-freezing in liquid nitrogen for molecular biology. Results The vigorous endurance training was resulted in increased left ventricular end-diastolic diameter, increased septal wall thickness and greater left ventricular mass index (Ex vs. Sed: 98±12 vs. 136±7 g/m2, p<0.05). Some degree of enhanced fibrosis was observed. Endurance training decreased heart rate both in whole animal and in vitro dog experiments. ECG recordings presented enhanced heart rate variability parameters, prolonged PQ (Ex vs. Sed: 98.3±2.9 vs. 116.7±3.6 ms, p<0.05), QRS (Ex vs. Sed : 60.5±2.4 vs 70.8±1.6 ms, p<0.05), QTc (Ex vs. Sed: 213.6±2.8 vs. 237.1±3.4 ms, p<0.05), Tp-Te (Ex vs. Sed: 27.9±2.5 vs.36.5±1.7 ms, p<0.05) intervals associated with significantly enhanced QT interval variability (eg. Ex vs. Sed: QT-STV, 2.5±0.2 vs. 3.6±0.4 ms, p<0.05), reflecting elevated level of repolarization dispersion. Ectopic activity was also enhanced in the exercised dog ventricle. Atropine treatment resulted in moderate heart rate increase in the Ex animals. Chronic endurance exercise elevated the proarrhythmic risk and consequent ventricular fibrillation in dogs subjected to burst electrical stimulation. Conclusion We developed a new animal model that shares similarities with the human endurance-trained athlete’s heart. The model represents increased arrhythmia susceptibility, an important clinical paradigm, and explores potential underlying mechanisms, including vagal enhancement, increased repolarization dispersion and enhanced fibrotic changes. Increased arrhythmia susceptibility is supported by the enhanced arrhythmia incidence in the exercised group. Similar changes may be present in young human top athletes, however further investigations are required.

Local areas of earlier repolarization cause epicardial repolarization heterogeneity in patients with apparently idiopathic ventricular fibrillation

Abstract Background Sudden cardiac arrest is often due to ventricular fibrillation (VF). In 5–10% of cases, no cause can be identified despite extensive cardiac examination, hence the designation idiopathic VF. Early repolarization with down sloping ST segments has been previously identified in patients with idiopathic VF. Early repolarization may increase repolarization heterogeneity with steep local repolarization time gradients, and thus form a substrate for idiopathic VF. Purpose To study the presence of local earlier repolarization and increased repolarization dispersion in idiopathic VF patients with noninvasive electrocardiographic imaging (ECGI). Methods A validated, non-commercial, potential-based formulation of ECGI was performed in 17 patients with idiopathic VF and 10 controls with no structural or electrical abnormalities. The ECGI measurement consisted of a body surface potential map with 184–256 electrodes in combination with a CT scan to obtain the torso and heart geometries. ECGI provided local epicardial repolarization times (RT) and RT isochrones. We determined the 1st (RT1%) and 99th percentile (RT99%) of RTs, the total epicardial RT dispersion (ERD: RT99%-RT1%), and the mean RT. Heart-rate corrected QT (QTc), TpTe intervals, and presence of the ER pattern were determined from the 12-lead ECG. All metrics were normalized to the body-surface Q. Results QTc and TpTe did not differ between the two groups (P=0.40 and P=0.83, respectively, Figure 1, panel A). One (10%) control subject and three (17.6%) idiopathic VF patients showed an ER pattern on the 12-lead ECG, with a down sloping ST segment only in 2/4 of the latter. With ECGI, the mean RT was similar between the groups (P=0.31), but the ERD was significantly increased in patients with idiopathic VF (P=0.01, figure 1, panel B). Moreover, RT1% was significantly lower in idiopathic VF patients in comparison to the controls (P=0.002), whereas the RT99% did not differ significantly (P=0.40). Subgroup analysis between ER positive and negative patients did not yield significantly different RT results. Conclusion Noninvasive ECGI, in contrast to the 12-lead ECG, revealed a wider range of epicardial RTs in patients with idiopathic VF, implying increased repolarization heterogeneity. This heterogeneity is caused by areas of earlier repolarization. Our data indicate the value of noninvasively diagnosing these repolarization abnormalities, and suggest promising potential value of the 1st percentile of RT to identify idiopathic VF patients with true early repolarization. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Figure 1

Changes in left ventricular electromechanical relations during targeted hypothermia

BackgroundTargeted hypothermia, as used after cardiac arrest, increases electrical and mechanical systolic duration. Differences in duration of electrical and mechanical systole are correlated to ventricular arrhythmias. The electromechanical window (EMW) becomes negative when the electrical systole outlasts the mechanical systole. Prolonged electrical systole corresponds to prolonged QT interval, and is associated with increased dispersion of repolarization and mechanical dispersion. These three factors predispose for arrhythmias. The electromechanical relations during targeted hypothermia are unknown.We wanted to explore the electromechanical relations during hypothermia at 33 °C. We hypothesized that targeted hypothermia would increase electrical and mechanical systolic duration without more profound EMW negativity, nor an increase in dispersion of repolarization and mechanical dispersion.MethodsIn a porcine model (n = 14), we registered electrocardiogram (ECG) and echocardiographic recordings during 38 °C and 33 °C, at spontaneous and atrial paced heart rate 100 beats/min. EMW was calculated by subtracting electrical systole; QT interval, from the corresponding mechanical systole; QRS onset to aortic valve closure. Dispersion of repolarization was measured as time from peak to end of the ECG T wave. Mechanical dispersion was calculated by strain echocardiography as standard deviation of time to peak strain.ResultsElectrical systole increased during hypothermia at spontaneous heart rate (p < 0.001) and heart rate 100 beats/min (p = 0.005). Mechanical systolic duration was prolonged and outlasted electrical systole independently of heart rate (p < 0.001). EMW changed from negative to positive value (− 20 ± 19 to 27 ± 34 ms, p = 0.001). The positivity was even more pronounced at heart rate 100 beats/min (− 25 ± 26 to 41 ± 18 ms, p < 0.001). Dispersion of repolarization decreased (p = 0.027 and p = 0.003), while mechanical dispersion did not differ (p = 0.078 and p = 0.297).ConclusionTargeted hypothermia increased electrical and mechanical systolic duration, the electromechanical window became positive, dispersion of repolarization was slightly reduced and mechanical dispersion was unchanged. These alterations may have clinical importance. Further clinical studies are required to clarify whether corresponding electromechanical alterations are accommodating in humans.

ECG markers of local but not global increase in dispersion of ventricular repolarization (simulation study)

BackgroundAn increase in local dispersion of repolarization (DOR) may contribute more to arrhythmogenesis as compared to changes of global DOR. The aim of this simulation study was to find ECG markers of local increase in DOR in conditions where global DOR remains normal. MethodsIn the framework of van Oosterom and Oostendorp ECGSIM model, the local DOR was increased in 10 different ventricular locations by (1) action potential duration (APD) shortening/lengthening both on epi- and endocardium, (2) epicardial APD shortening, and (3) endocardial APD shortening. The simulation cases where the increase in local DOR was accompanied by increase in global DOR were excluded from consideration. T-wave parameters were analyzed in the simulated precordial and anatomically ordered limb leads. ResultsThe increase in local DOR resulted in increased lead-to‑lead differences in Tpeak and Tend instants in 28 out of 32 simulated scenarios, and in an increased dispersion of Tpeak-Tend interval throughout 12 standard leads in 8 out of 32 simulated scenarios. In all simulations, the global DOR measured as a difference between earliest and latest repolarization times and standard APD deviation was the same. ConclusionsThe local increase in DOR was expressed in increased lead-to‑lead differences in Tpeak and Tend instants between adjacent anatomically ordered standard leads (aVL, I, aVR(−), II, aVF, III, and V1-V6), even if global DOR, Tpeak-Tend interval and Tpeak-Tend dispersion were within a normal range.

Effect of Thoracic Epidural Anesthesia on Ventricular Excitability in a Porcine Model.

Imbalances in the autonomic nervous system, namely, excessive sympathoexcitation, contribute to ventricular tachyarrhythmias. While thoracic epidural anesthesia clinically suppresses ventricular tachyarrhythmias, its effects on global and regional ventricular electrophysiology and electrical wave stability have not been fully characterized. The authors hypothesized that thoracic epidural anesthesia attenuates myocardial excitability and the proarrhythmic effects of sympathetic hyperactivity. Yorkshire pigs (n = 15) had an epidural catheter inserted (T1 to T4) and a 56-electrode sock placed on the heart. Myocardial excitability was measured by activation recovery interval, dispersion of repolarization, and action potential duration restitution at baseline and during programed ventricular extrastimulation or left stellate ganglion stimulation, before and 30 min after thoracic epidural anesthesia (0.25% bupivacaine). After thoracic epidural anesthesia infusion, there was no change in baseline activation recovery interval or dispersion of repolarization. During programmed ventricular extrastimulation, thoracic epidural anesthesia decreased the maximum slope of ventricular electrical restitution (0.70 ± 0.24 vs. 0.89 ± 0.24; P = 0.021) reflecting improved electrical wave stability. Thoracic epidural anesthesia also reduced myocardial excitability during left stellate ganglion stimulation-induced sympathoexcitation through attenuated shortening of activation recovery interval (-7 ± 4% vs. -4 ± 3%; P = 0.001), suppression of the increase in dispersion of repolarization (313 ± 293% vs. 185 ± 234%; P = 0.029), and reduction in sympathovagal imbalance as measured by heart rate variability. Our study describes the electrophysiologic mechanisms underlying antiarrhythmic effects of thoracic epidural anesthesia during sympathetic hyperactivity. Thoracic epidural anesthesia attenuates ventricular myocardial excitability and induces electrical wave stability through its effects on activation recovery interval, dispersion of repolarization, and the action potential duration restitution slope.

The QUIDAM study: Hydroquinidine therapy for the management of Brugada syndrome patients at high arrhythmic risk

Although the implantable cardioverter-defibrillator (ICD) remains the main therapy for Brugada syndrome (BrS), it does not reduce life-threatening ventricular arrhythmia. Based on pathophysiologic mechanisms, hydroquinidine (HQ) has been suggested for effective prevention of arrhythmia. The purpose of this study was to provide evidence-based data supporting HQ use to prevent life-threatening ventricular arrhythmia in high-risk patients with BrS. We performed a prospective multicenter randomized (HQ vs placebo) double-blind study with two 18-month crossover phases in patients with BrS and implanted with an ICD. Among the 50 patients enrolled (mean age 47.0 ± 11.4 years, 42 [84%] male), 26 (52%) fully completed both phases. Thirty-four (68%) presented HQ-related side effects, mainly gastrointestinal, which led to discontinuation of the therapy in 13 (26%). HQ lengthened the QTc interval (409 ± 32 ms vs 433 ± 37 ms; P = .027) and increased repolarization dispersion as evaluated by Tpe max in precordial leads (89 ± 15 ms vs 108 ± 27 ms; P <.0001) with no significant changes in J-point elevation. During the 36-month follow-up, 1 appropriate ICD shock (0.97% event per year), 1 self-terminating ventricular fibrillation, and 1 inappropriate ICD shock occurred under placebo therapy. No arrhythmic events were reported under HQ therapy. Although HQ seems to be effective in preventing life-threatening ventricular arrhythmia, it could not be an alternative for ICD implantation. Its frequent side effects greatly reduce its probable compliance and therefore do not reveal a significant effect. HQ increases repolarization dispersal with no changes in BrS pattern, which could indicate a more complex action of HQ than its Ito blocking effect alone.

Colchicine Increases Ventricular Vulnerability in an Experimental Whole‐Heart Model

The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole-heart model. Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, colchicine was administered in two concentrations (1 and 3 μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose-dependent significant decrease of effective refractory period (ERP; 1 μM: -19 ms, 3 μM: -22 ms; p < 0.05). In the present study, acute infusion of colchicine in isolated rabbit hearts resulted in a reduction of ERP in the presence of a stable myocardial repolarization. This led to a significantly elevated inducibility of ventricular fibrillation. In 4 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a pro-arrhythmic or toxic effect of colchicine and underline that further clinical studies on potential adverse effects should be conducted before the drug can be recommended for routine use after atrial fibrillation ablation.

Experimental evidence for a severe proarrhythmic potential of levosimendan

BackgroundThe calcium sensitizer levosimendan is established for therapy of acutely decompensated congestive heart failure. Clinical experience suggests a possible proarrhythmic potential. The aim of the present study was to assess possible proarrhythmic effects and underlying electrophysiological mechanisms. Methods and resultsTen rabbit hearts were isolated and Langendorff-perfused. Thereafter, levosimendan was infused in 3 concentrations (0.5, 1, and 2μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a dose-dependent reduction of QT interval (0.5μM: −27ms, 1μM:-33ms, 2μM: −77ms; p<0.05) and action potential duration at 90% of repolarization (APD90; 0.5μM: −12ms, 1μM: −12ms, 2μM: −20ms). There was no significant increase in dispersion of repolarization. The described abbreviation of myocardial repolarization was accompanied by a significant decrease of effective refractory period (ERP; 0.5μM: −16ms, 1μM: −20ms, 2μM:−27ms; p<0.05).Under baseline conditions, ventricular fibrillation was inducible by programmed stimulation and aggressive burst stimulation in 3 of 10 hearts (4 episodes). After application of 1μM levosimendan, 8 of 10 control hearts were inducible (27 episodes). Of note, in 8 of 10 hearts after infusion of up to 2μM levosimendan, incessant ventricular fibrillation that could not be terminated by multiple external defibrillations occurred. ConclusionIn the present study, acute infusion of levosimendan resulted in an abbreviation of ventricular repolarization and a reduction of ERP. This led to a significantly elevated inducibility of ventricular fibrillation. In 8 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a proarrhythmic effect of levosimendan and might explain an increased mortality that coincided levosimendan treatment in a few small clinical studies.

Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models.

Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT). Although the CACNA1C mutations were well identified in patients with cardiac arrhythmias, mechanisms by which cardiac arrhythmias are generated in such genetic mutation conditions remain unclear. In this study, we identified a novel mechanism of VT resulted from enhanced repolarization dispersion which is a key factor for arrhythmias in the CACNA1C G1911R mutation using multi-scale computational models of the human ventricle. The increased calcium influx in the mutation prolonged action potential duration (APD), produced steepened action potential duration restitution (APDR) curves as well as augmented membrane potential differences among different cell types during repolarization, increasing transmural dispersion of repolarization (DOR) and the spatial and temporal heterogeneity of cardiac electrical activities. Consequentially, the vulnerability to unidirectional conduction block in response to a premature stimulus increased at tissue level in the G1911R mutation. The increased functional repolarization dispersion anchored reentrant excitation waves in tissue and organ models, facilitating the initiation and maintenance of VT due to less meandering rotor tip. Thus, the increased repolarization dispersion caused by the G1911R mutation is a primary factor that may primarily contribute to the genesis of cardiac arrhythmias in Timothy Syndrome.

Ventricular Repolarization: Epidemiology and Clinical Correlates among Type-2 Diabetics with Uncontrolled Arterial Hypertension in Western Region of the Republic of Macedonia

This study aimed to describe the epidemiology of repolarization dispersion (QT dispersion and Tpeak-Tend dispersion) and further describe their associated clinical correlates among uncontrolled arterial hypertension in type-2 Diabetics patient, in western region of the Republic of Macedonia. Abnormal ventricular repolarization is associated with increased cardiovascular risk. Data relating to the frequency of increased repolarization dispersion, among uncontrolled arterial hypertension in type-2 Diabetics patient in western region of the Republic of Macedonia, are scarce. A total of 600 patients were enrolled into this observation study. Study participans were selected among primary care patient, who were receiving ongoing care for diabetes mellitus and hypertension during 1 calendar year. Twelve lead resting electrocardiography, QT, QTc, Tpeak-Tend-intervals and dispersions, were determined manually, and were compared between groups. Patients with uncontrolled BP have greater frequency of: prolonged QTc.max.interval, (61.3% vs.33.6%; p = 0.0005), prolonged Tpeak-Tend interval (65.3% vs. 34.7%; p = 0.005), increased dispersion of QTc. interval (65.9% vs. 34.1%; p = 0.00), increased disperion of Tpeak-Tend interval (65.5% vs. 34.5%; p = 0.002). Females with uncontrolled BP have greater frequency of: increased dispersion of QTc. interval (61.2% vs. 38%; p = 0.02), increased dispersion of Tpeak-Tend interval (63.1% vs. 31.5%; p = 0.008). Hypertensive diabetic patients with uncontrolled BP and abnormal ventricular repolarization have greater BMI (p = 0.000; 95%CI 3.849 - 7.871), longer duration of D.M (p = 0.000; 95%CI 1.600 - 1.981), longer duration of arterial hypertension (p = 0.000; 95%CI 1.468 - 1.850) and less controlled glycemia (p = 0.000; 95%CI 1.556 - 3.004). Frequency of increased set of electrophysiological parameters that indicate a prolonged and more heterogeneous repolarization among diabetic patients with uncontrolled BP, is considerable high and seems to be significantly associated with demographic and clinical parameters: gender, BMI, duration of diabetes, duration of BP and glycemic control.

Electrophysiological profile of vernakalant in an experimental whole-heart model: the absence of proarrhythmia despite significant effect on myocardial repolarization

The most recent European Society of Cardiology (ESC) update on atrial fibrillation has introduced vernakalant (VER) for pharmacological cardioversion of atrial fibrillation. The aim of the present study was to investigate the safety profile of VER in a sensitive model of proarrhythmia. In 36 Langendorff-perfused rabbit hearts, VER (10, 30 µM, n = 12); ranolazine (RAN, 10, 30 µM, n = 12), or sotalol (SOT, 50; 100 µM, n = 12) were infused after obtaining baseline data. Monophasic action potentials and a 12-lead electrocardiogram showed a significant QT prolongation after application of VER as compared with baseline (10 µM: +25 ms, 30 µM: +50 ms, P < 0.05) accompanied by an increase of action potential duration (APD). The increase in APD90 was accompanied by a more marked increase in effective refractory period (ERP) leading to a significant increase in post-repolarization refractoriness (PRR, 10 µM: +30 ms, 30 µM: +36 ms, P < 0.05). Vernakalant did not affect the dispersion of repolarization. Lowered potassium concentration in bradycardic hearts did not provoke early afterdepolarizations (EADs) or polymorphic ventricular tachycardia (pVT). Comparable results were obtained with RAN. Hundred micromolars of SOT led to an increase in QT interval (+49 ms) and APD90 combined with an increased ERP and PRR (+23 ms). In contrast to VER, 100 µM SOT led to a significant increase in dispersion of repolarization and to the occurrence of EAD in 10 of 12 and pVT in 8 of 12 hearts. In the present study, application of VER and SOT led to a comparable prolongation of myocardial repolarization. Both drugs increased the PRR. However, VER neither affect the dispersion of repolarization nor induce EAD and therefore did not cause proarrhythmia.

Mild hypothermia decreases arrhythmia susceptibility in a canine model of global myocardial ischemia*

Although the majority of sudden cardiac arrests occur in patients with ischemic heart disease, the effect of therapeutic hypothermia on arrhythmia susceptibility during acute global ischemia is not well understood. While both ischemia and severe hypothermia are arrhythmogenic, patients undergoing therapeutic hypothermia do not have an increase in arrhythmias, despite the fact that most sudden cardiac arrest occur in the setting of ischemia. We hypothesized that mild hypothermia induced prior to myocardial ischemia and reperfusion will have a beneficial effect on ischemia-related arrhythmia substrates. We developed a model of global ischemia and reperfusion in the canine wedge preparation to study the transmural electrophysiologic effects of ischemia at different temperatures. Animal study. Male mongrel dogs. Canine left ventricle wedge preparations at 1) control (36°C) or 2) mild hypothermia, to simulate temperatures used in therapeutic hypothermia (32°C), were subjected to 15 mins of no-flow ischemia and subsequently reperfused. Optical action potentials were recorded spanning the transmural wall of left ventricle. Action potential duration for epicardial, mid-myocardial, and epicardial cells was measured. Transmural dispersion of repolarization and conduction velocity were measured at baseline, during ischemia, and during reperfusion. No difference was seen at baseline for conduction velocity or dispersion of repolarization between groups. Conduction velocity decreased from 0.46 ± 0.02 m/sec to 0.23 ± 0.07 m/sec, and dispersion of repolarization increased from 30 ± 5 msecs to 57 ± 4 msecs in the control group at 15 mins of ischemia. Mild hypothermia attenuated both the ischemia-induced conduction velocity slowing (decreasing from 0.44 ± 0.02 m/sec to 0.35 ± 0.03 m/sec; p = .019) and the ischemia-induced increase in dispersion of repolarization (25 ± 3 msecs to 37 ± 7 msecs; p = .037). Epicardial conduction block was observed in six of seven preparations of the control group, but no preparations in the mild hypothermia group developed conduction block (0/6). Mild hypothermia attenuated ischemia-induced increase in dispersion of repolarization, conduction slowing, and block, which are known mechanisms of arrhythmogenesis in ischemia. These data suggest that therapeutic hypothermia may decrease arrhythmogenesis during myocardial ischemia.

Electrophysiologic Profile of Dronedarone on the Ventricular Level

Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg · kg(-1) · d(-1)) and amiodarone (A; n = 20; 50 mg · kg(-1) · d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 μM; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 μM), +56 milliseconds (100 μM); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.

Abstract 256: Therapeutic Hypothermia Decreases Arrhythmia Substrates by Attenuating Repolarization Current I K,ATP During Myocardial Ischemia

Background: While hypothermia is arrhythmogenic, the effect of therapeutic hypothermia (TH) performed after cardiac arrest on susceptibility to arrhythmias is not well understood. Clinically, patients do not have an increase in arrhythmias, and it is possible that TH may be cardioprotective. The repolarization current I K,ATP is activated only during ischemia where it heterogeneously shortens action potentials increasing dispersion of repolarization (DOR). Since I K,ATP is attenuated at cooler temperatures, we hypothesized that the antiarrhythmic effect of TH during ischemia may be mediated by attenuation of I K,ATP activation. To test this hypothesis, a model of no flow global ischemia in the canine wedge preparation was created to study the effects of ischemia on all cell types spanning the transmural wall. Methods: Optical action potentials were recorded transmurally with high spatial (1 mm), temporal (.5 ms) and voltage (.5mv) resolution. To block I K,ATP, glibenclamide (10 µmol) was used at both 36 o C (normal temperature, NT+ I K,ATP block, n=3) and 32 o C (TH+ I K,ATP block, n=3) during 15 min of no flow global ischemia. I K,ATP blockade was compared to prior controls (NT=7, TH=6). Action potential duration (APD) for epicardial, mid-myocardial, and epicardial cells, DOR, and conduction velocity (CV) were measured for all conditions. Results: There was no difference in DOR between the 4 groups prior to ischemia. NT+ I K,ATP block attenuated ischemia-induced increase in DOR compared to NT controls (22±4 ms to 25±5 ms vs. 30±5 to 57±5 ms, p=.002). NT+ I K,ATP block also attenuated ischemia-induced conduction slowing (44±2 to 30±3 cm/s vs 34±5 to 18±3 cm/s, p=.03). Addition of I K,ATP block to TH did not further attenuate the DOR or CV vs. TH alone (p&gt;0.05). Ischemia-induced epicardial conduction bock was attenuated by I K,ATP blockade, (0/3 I K,ATP block vs. 6/7 NT) Epicardial block was attenuated in both TH groups. Conclusions: I K,ATP blockade attenuates ischemia-induced DOR, conduction slowing, and epicardial conduction block, reproducing the effect of TH. This suggests that hypothermia-induced attenuation of I K,ATP may play a role in the mechanism of attenuation of ischemia-induced arrhythmias observed in TH.

G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure

G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10μg/kg G-CSF s.c. over 17±4days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33±12ms; p<0.01). Moreover, a significant increase in dispersion of repolarization contributed to a significantly higher rate of ventricular tachyarrhythmias in CHF. G-CSF-pre-treated hearts showed a further increase in prolongation of repolarization as compared with S and CHF. The further increase in dispersion of repolarization [S-G-CSF: +23±9ms (spatial), +13±7ms (temporal); CHF-G-CSF: +38±14ms (spatial), +10±4ms (temporal); p<0.05 as compared with S and CHF], increased the incidence of ventricular tachyarrhythmias. In summary, chronic G-CSF treatment has moderate beneficial effects on parameters potentially related to hemodynamic function in the non-ischemic rabbit CHF model. However, a significant reduction of repolarization reserve might seriously challenge its suitability as a therapeutic agent for chronic CHF therapy.

A new mechanism preventing proarrhythmia in chronic heart failure: rapid phase‐III repolarization explains the low proarrhythmic potential of amiodarone in contrast to sotalol in a model of pacing‐induced heart failure

Life-threatening arrhythmias are a major problem in chronic heart failure (CHF). The aim of the present study was to investigate the mechanism underlying the low proarrhythmic potential of amiodarone in a model of pacing-induced heart failure. Heart failure was induced in 35 female rabbits by rapid ventricular pacing, resulting in a significant decrease of ejection fraction. Thirty-four rabbits were sham-operated. In 17 of 35 CHF-rabbits and 20 of 34 'sham'-rabbits, amiodarone (50 mg/kg/day) was fed for 6 weeks. Eight monophasic action potentials and a simultaneously recorded 12-lead electrocardiogram showed prolongation of QT-interval and action potential duration (APD(90)) in all failing hearts (P< 0.05). Amiodarone pre-treatment led to a prolongation of APD(90) (+19 ms) as compared with sham-controlled hearts but showed only a marginal effect on APD(90) in failing hearts. Infusion of sotalol (50-100 µM) led to a significant prolongation of APD(90) in sham and a further prolongation of APD(90) in failing hearts [+55 ms (50 µM); +70 ms (100 µM); P< 0.01 as compared with sham hearts]. Sotalol led to a triangular action potential configuration in sham and failing hearts, whereas amiodarone did not cause triangularization but caused a rapid phase-III repolarization. Moreover, amiodarone did not increase dispersion of repolarization either in sham or in failing hearts. Infusion of sotalol led to a significant increase in dispersion of repolarization in sham (+29 ms) and a further increase in failing hearts (+67 ms; P< 0.05). Chronic amiodarone results in a rapid phase-III-repolarization and does not increase dispersion of repolarization. These electrophysiological findings are present in healthy hearts and are preserved in heart failure. This contributes to the low proarrhythmic potential of amiodarone in heart failure.

Beat-to-beat T-wave amplitude variability in the long QT syndrome

Long QT syndrome (LQTS) is a primary electrical disease characterized by QT prolongation and increased repolarization dispersion leading to T-wave amplitude beat-to-beat changes. We aimed to quantify beat-to-beat T-wave amplitude variability from ambulatory Holter recordings in genotyped LQTS patients. Seventy genotyped LQTS patients (mean age 23 +/- 15 years, 42 males, 50% LQT1, 39% LQT2, and 11% LQT3) and 70 normal matched control subjects underwent a 24-h digital Holter recording. Using the Tvar software (Ela Medical, Sorin group), the beat-to-beat variance of the T-wave amplitude (TAV in microV) [corrected] was assessed on 50-ms consecutive clusters during three 1-h periods: one with around average diurnal heart rate (Day Fast), one nocturnal period (Night), and one diurnal period with around average nocturnal heart rate (Day Slow). TAV was increased in LQTS patients during the two diurnal periods but not at night (during the Day Fast period, mean TAV was 34 +/- 20 microV [corrected] in LQTS patients vs. 27 +/- 10 microV [corrected] in controls, P < 0.05). This effect depended on the genotype. In LQT1, TAV was larger when compared with controls for both Day Fast and Slow periods, but in LQT2 only Day Fast shows higher TAV. Oppositely, in LQT3 the TAV was higher than in the control group during the Day slow period (mean TAV = 34 +/- 20 vs. 25 +/- 8 microV [corrected] in controls, P < 0.05). In genotyped LQTS patients beat-to-beat T-wave amplitude variability was increased when compared with control subjects. That pattern was modulated by circadian influences in a gene-dependent manner.

Reduction of Dispersion of Repolarization and Prolongation of Postrepolarization Refractoriness Explain the Antiarrhythmic Effects of Quinidine in a Model of Short QT Syndrome

Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. Pinacidil, an I(K-ATP) channel opener, was administered in increasing concentrations (50-100 microM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I(Kr) blocker sotalol (100 microM) and the class I antiarrhythmic drugs flecainide (2 microM) and quinidine (0.5 microM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.